EP1082460A1 - Nouveau procede de diagnostic, de surveillance et de stadification du cancer de la prostate - Google Patents

Nouveau procede de diagnostic, de surveillance et de stadification du cancer de la prostate

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Publication number
EP1082460A1
EP1082460A1 EP99921946A EP99921946A EP1082460A1 EP 1082460 A1 EP1082460 A1 EP 1082460A1 EP 99921946 A EP99921946 A EP 99921946A EP 99921946 A EP99921946 A EP 99921946A EP 1082460 A1 EP1082460 A1 EP 1082460A1
Authority
EP
European Patent Office
Prior art keywords
psg
levels
patient
cancer
tissue
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99921946A
Other languages
German (de)
English (en)
Other versions
EP1082460A4 (fr
Inventor
Shujath Ali
Susana Salceda
Yongming Sun
Robert Apartment 4305 CAFFERKEY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Diadexus Inc
Original Assignee
Diadexus Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Diadexus Inc filed Critical Diadexus Inc
Priority to EP05019760A priority Critical patent/EP1621639A3/fr
Publication of EP1082460A1 publication Critical patent/EP1082460A1/fr
Publication of EP1082460A4 publication Critical patent/EP1082460A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57434—Specifically defined cancers of prostate
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification

Definitions

  • This invention relates, in part, to newly developed assays for detecting, diagnosing, monitoring, staging, and prognosticating cancers, particularly prostate cancer.
  • Cancer of the prostate is the most prevalent malignancy in adult males, excluding skin cancer, and is an increasingly prevalent health problem in the United States. In 1996, it was estimated that in the United States, 41,400 deaths would result from this disease, indicating that prostate cancer is second only to lung cancer as the most common cause of death in the same population. If diagnosed and treated early, when the cancer is still confined to the prostate, the chance of cure is significantly higher.
  • a common classification of the spread of prostate cancer was developed by the American Urological Association (AUA) .
  • the AUA classification divides prostate tumors into four stages, A to D.
  • Stage A microscopic cancer within prostate, is further subdivided into stages Al and A2.
  • Stage Al is a well-differentiated cancer confined to one site within the prostate.
  • Treatment is generally observation, radical prostatectomy, or radiation.
  • Sub-stage A2 is a moderately to poorly differentiated cancer at multiple sites within the prostate. Treatment is radical prostatectomy or radiation.
  • Stage B palpable lump within the prostate, is further subdivided into stages Bl and B2.
  • sub-stage Bl the cancer forms a small nodule in one lobe of the prostate.
  • the cancer forms large or multiple nodules, or occurs in both lobes of the prostate.
  • Treatment for both sub- stages Bl and B2 is either radical prostatectomy or radiation.
  • Stage C is a large cancer mass involving most or all of the prostate and is further subdivided into two stages.
  • the cancer forms a continuous mass that may have extended beyond the prostate.
  • sub-stage C2 the cancer forms a continuous mass that invades the surrounding tissue. Treatment for both these sub-stages is radiation with or without drugs.
  • the fourth stage is metastatic cancer and is also subdivided into two stages.
  • sub-stage Dl the cancer appears in the lymph nodes of the pelvis.
  • sub-stage D2 the cancer involves tissues beyond lymph nodes. Treatment for both these sub-stages is systemic drugs to address the cancer as well as pain.
  • PSG Prostate Specific Genes
  • the seven PSGs as used herein means the native mRNAs encoded by the genes comprising any of the polynucleotide sequences of SEQ ID NO: 1, 2, 3, 4, 5, 6 or 7 or levels of the genes comprising any of the polynucleotide sequences of SEQ ID NO: 1, 2, 3, 4, 5, 6 or 7.
  • Another object of the present invention is to provide a method of diagnosing metastatic prostate cancer in a patient which comprises measuring PSG levels in a sample of cells, tissue, or bodily fluid from the patient and comparing the measured PSG levels with levels of PSG in preferably the same cells, tissue, or bodily fluid type of a control, wherein an increase in measured PSG levels in the patient versus levels of PSG in the control is associated with a cancer which has metastasized.
  • Another object of the present invention is to provide a method of staging prostate cancer in a patient which comprises identifying a patient having prostate cancer, measuring levels of PSG in a sample of cells, tissues, or bodily fluid obtained from the patient, and comparing the measured PSG levels with levels of PSG in preferably the same cells, tissue or bodily fluid type of a control.
  • An increase in measured PSG levels in the patient versus PSG levels in the control can be associated with a cancer which is progressing while a decrease or equivalent level of PSG measured in the patient versus the control can be associated with a cancer which is regressing or in remission.
  • Another object of the present invention is to provide a method of monitoring prostate cancer in a patient for the onset of metastasis.
  • the method comprises identifying a patient having prostate cancer that is not known to have metastasized, periodically measuring levels of PSG in a sample of cells, tissues, or bodily fluid obtained from the patient, and comparing the measured PSG levels with levels of PSG in preferably the same cells, tissue, or bodily fluid type of a control, wherein an increase in measured PSG levels versus control PSG levels is associated with a cancer which has metastasized.
  • Yet another object of the present invention is to provide a method of monitoring the change in stage of prostate cancer in a patient which comprises identifying a patient having prostate cancer, periodically measuring levels of PSG in a sample of cells, tissue, or bodily fluid obtained from the patient, and comparing the measured PSG levels with levels of PSG in preferably the same cells, tissues, or bodily fluid type of a control wherein an increase in measured PSG levels versus the control PSG levels is associated with a cancer which is progressing and a decrease in the measured PSG levels versus the control PSG levels is associated with a cancer which is regressing or in remission.
  • the present invention relates to diagnostic assays and methods, both quantitative and qualitative for detecting, diagnosing, monitoring, staging, and prognosticating cancers by comparing levels of PSG measured in a patient with levels of PSG in a control.
  • levels of PSG means levels of the native protein expressed by the gene comprising the polynucleotide sequence of any of SEQ ID NO: 1, 2, 3, 4, 5, 6 or 7.
  • levels of PSG is levels of the native mRNA encoded by the gene comprising any of the polynucleotide sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6 or 7 or levels of the gene comprising any of the polynucleotide sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6 or 7.
  • levels are preferably measured in at least one of cells, tissues and/or bodily fluids, and includes determination of both normal and abnormal levels of PSGs.
  • a diagnostic assay in accordance with the invention for diagnosing overexpression of PSG protein compared to control bodily fluids, cells, or tissue samples may be used to diagnose the presence of cancers, including prostate cancer. Any of the seven PSGs may be measured alone in the methods of the invention, all together or in various combinations of the seven PSGs.
  • control it is meant a human patient without cancer and/or non cancerous samples from the patient, also referred to herein as a normal human control; in the methods for diagnosing or monitoring for metastasis, control may also include samples from a human patient that is determined by reliable methods to have prostate cancer which has not metastasized.
  • All the methods of the present invention may optionally include measuring the levels of other cancer markers as well as PSG.
  • Other cancer markers, in addition to PSG, useful in the present invention will depend on the cancer being tested and are known to those of skill in the art. For example, simultaneous testing for increases in PSA as well as increases in PSG are also within the scope of the present invention and believed to provide a higher level of assurance that such cancer being tested is metastatic or the onset of metastasis has occurred.
  • the present invention provides methods for diagnosing the presence of prostate cancer by analyzing for changes in levels of PSG in cells, tissues or bodily fluids compared with levels of PSG in cells, tissues or bodily fluids of preferably the same type from a normal human control, wherein an increase in levels of PSG in the patient versus the normal human control is associated with the presence of prostate cancer.
  • a positive result indicating the patient being tested has cancer is one in which cells, tissues, or bodily fluid levels of the cancer marker, such as PSG, are at least two times higher, and most preferably are at least five times higher, than in preferably the same cells, tissues, or bodily fluid of a normal human control.
  • the present invention also provides a method of diagnosing metastatic prostate cancer in a patient having prostate cancer which has not yet metastasized for the onset of metastasis.
  • a human cancer patient suspected of having prostate cancer which may have metastasized (but which was not previously known to have metastasized) is identified. This is accomplished by a variety of means known to those of skill in the art.
  • patients are typically diagnosed with prostate cancer following traditional detection methods.
  • determining the presence of PSG in cells, tissues, or bodily fluid is particularly useful for discriminating between prostate cancer which has not metastasized and prostate cancer which has metastasized.
  • Existing techniques have difficulty discriminating between prostate cancer which has metastasized and prostate cancer which has not metastasized and proper treatment selection is often dependent upon such knowledge.
  • the cancer marker levels measured in such cells, tissue, or bodily fluid are PSGs, and are compared with levels of PSG in preferably the same cells, tissue, or bodily fluid type of a normal human control. That is, if the cancer marker being observed is just PSG in serum, this level is preferably compared with the level of PSG in serum of a normal human patient. An increase in the PSG in the patient versus the normal human control is associated with prostate cancer which has metastasized.
  • a positive result indicating the cancer in the patient being tested or monitored has metastasized is one in which cells, tissues, or bodily fluid levels of the cancer marker, such as PSG, are at least two times higher, and most preferable are at least five times higher, than in preferably the same cells, tissues, or bodily fluid of a normal patient.
  • the invention also provides a method of staging prostate cancer in a human patient.
  • the method comprises identifying a human patient having such cancer and analyzing a sample of cells, tissues, or bodily fluid from such patient for PSG. Then, the method compares PSG levels in such cells, tissues, or bodily fluid with levels of PSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in PSG levels in the patient versus the normal human control is associated with a cancer which is progressing and a decrease in the levels of PSG is associated with a cancer which is regressing or in remission.
  • a method of monitoring prostate cancer in a human having such cancer for the onset of metastasis comprises identifying a human patient having such cancer that is not known to have metastasized; periodically analyzing a sample of cells, tissues, or bodily fluid from such patient for PSG; and comparing the PSG levels in such cells, tissue, or bodily fluid with levels of PSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in PSG levels in the patient versus the normal human control is associated with a cancer which has metastasized.
  • a method of monitoring the change in stage of prostate cancer in a human having such cancer comprises identifying a human patient having such cancer; periodically analyzing a sample of cells, tissue, or bodily fluid from such patient for PSG; comparing the PSG levels in such cells, tissue, or bodily fluid with levels of PSG in preferably the same patient.
  • Assay techniques that can be used to determine levels of gene expression, such as PSG of the present invention, in a sample derived from a host are well-known to those of skill in the art. Such assay methods include radioimmunoassays, reverse transcriptase PCR (RT-PCR) assays, immunohistochemistry assays, in si tu hybridization assays, competitive-binding assays, Western Blot analyses and ELISA assays. Among these, ELISAs are frequently preferred to diagnose a gene's expressed protein in biological fluids.
  • An ELISA assay initially comprises preparing an antibody, if not readily available from a commercial source, specific to PSG, preferably a monoclonal antibody.
  • reporter antibody generally is prepared which binds specifically to PSG.
  • the reporter antibody is attached to a detectable reagent such as radioactive, fluorescent or enzymatic reagent, for example horseradish peroxidase enzyme or alkaline phosphatase.
  • antibody specific to PSG is incubated on a solid support, e.g., a polystyrene dish, that binds the antibody. Any free protein binding sites on the dish are then covered by incubating with a non-specific protein such as bovine serum albumin.
  • a non-specific protein such as bovine serum albumin.
  • the sample to be analyzed is incubated in the dish, during which time PSG binds to the specific antibody attached to the polystyrene dish. Unbound sample is washed out with buffer.
  • a reporter antibody specifically directed to PSG and linked to horseradish peroxidase is placed in the dish resulting in binding of the reporter antibody to any monoclonal antibody bound to PSG. Unattached reporter antibody is then washed out.
  • Reagents for peroxidase activity including a colorimetric substrate are then added to the dish.
  • the amount of color developed in a given time period is proportional to the amount of PSG protein present in the sample. Quantitative results typically are obtained by reference to a standard curve .
  • a competition assay may be employed wherein antibodies specific to PSG attached to a solid support and labeled PSG and a sample derived from the host are passed over the solid support and the amount of label detected attached to the solid support can be correlated to a quantity of PSG in the sample.
  • Nucleic acid methods may be used to detect PSG mRNA as a marker for prostate cancer.
  • Polymerase chain reaction (PCR) and other nucleic acid methods such as ligase chain reaction (LCR) and nucleic acid sequence based amplification (NASABA)
  • PCR polymerase chain reaction
  • LCR ligase chain reaction
  • NASABA nucleic acid sequence based amplification
  • RT-PCR reverse- transcriptase PCR
  • cDNA complementary DNA
  • RT-PCR can thus reveal by amplification the presence of a single species of mRNA. Accordingly, if the mRNA is highly specific for the cell that produces it, RT-PCR can be used to identify the presence of a specific type of cell.
  • Hybridization to clones or oligonucleotides arrayed on a solid support can be used to both detect the expression of and quantitate the level of expression of that gene.
  • a cDNA encoding the PSG gene is fixed to a substrate.
  • the substrate may be of any suitable type including but not limited to glass, nitrocellulose, nylon or plastic.
  • At least a portion of the DNA encoding the PSG gene is attached to the substrate and then incubated with the analyte, which may be RNA or a complementary DNA (cDNA) copy of the RNA, isolated from the tissue of interest.
  • Hybridization between the substrate bound DNA and the analyte can be detected and quantitated by several means including but not limited to radioactive labeling or fluorescence labeling of the analyte or a secondary molecule designed to detect the hybrid. Quantitation of the level of gene expression can be done by comparison of the intensity of the signal from the analyte compared with that determined from known standards. The standards can be obtained by in vitro transcription of the target gene, quantitating the yield, and then using that material to generate a standard curve.
  • Bodily fluids useful in the present invention include blood, urine, saliva, or any other bodily secretion or derivative thereof.
  • Blood can include whole blood, plasma, serum, or any derivative of blood.
  • Subsetting is similar to library comparison but allows the identification of clones expressed in a pool of libraries and absent or expressed at a lower level in a second pool of libraries.
  • Transcript Imaging lists all of the clones in a single library or a pool of libraries based on abundance. Individual clones can then be examined using Electronic Northerns to determine the tissue sources of their component ESTs.
  • Incyte has identified subsets of ESTs with a potential protein function based on homologies to known proteins. Some examples in this database include Transcription Factors and Proteases. Some leads were identified by searching in this database for clones whose component ESTs showed disease specificity.
  • EXAMPLE 2 Measurement of SEQ ID NO:l; Clone ID # 1550426; Gene ID #244673 (prolOl)
  • the example is carried out using standard techniques, which are well known and routine to those of skill in the art, except where otherwise described in detail. Routine molecular biology techniques of the following example are carried out as described in standard laboratory manuals, such as Sambrook et al., MOLECULAR CLONING: A LABORATORY MANUAL, 2nd Ed.; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) .
  • Real-time quantitative PCR with fluorescent Taq an probes is a quantitative detection system utilizing the 5'- 3' nuclease activity of Taq DNA polymerase.
  • the method uses an internal fluorescent oligonucleotide probe (Taqman) labeled with a 5' reporter dye and a downstream, 3' quencher dye.
  • Taqman internal fluorescent oligonucleotide probe
  • the 5' -3' nuclease activity of Taq DNA polymerase releases the reporter, whose fluorescence can then be detected by the laser detector of the Model 7700 Sequence Detection System (PE Applied Biosyste s, Foster City, CA, USA) .
  • Amplification of an endogenous control is used to standardize the amount of sample RNA added to the reaction and normalize for Reverse Transcriptase (RT) efficiency.
  • Either cyclophilin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or 18S ribosomal RNA (rRNA) is used as this endogenous control.
  • GPDH glyceraldehyde-3-phosphate dehydrogenase
  • rRNA 18S ribosomal RNA
  • RNA was extracted from tumor and matched normal adjacent tissues and from unmatched tumor and normal tissues.
  • first strand cDNA was prepared with reverse transcriptase and the polymerase chain reaction carried out using primers and Taqman probe specific to prolOl (SEQ ID NO:l).
  • the results were obtained using the ABI PRISM 7700 Sequence Detector.
  • the absolute numbers are relative levels of expression of prolOl (SEQ ID NO:l) compared to the calibrator.
  • RNA samples were generated by pooling samples from a particular tissue from different individuals.
  • Table 2 cannot be directly compared to the values shown in Table 3.
  • the absolute numbers in Table 3 are relative levels of expression of prolOl (SEQ ID NO:l) compared to kidney (calibrator), in 60 pairs of matching samples. Each matching pair contains the cancer sample for a particular tissue and the normal adjacent sample for that same tissue from the same individual. The results from 3 unmatched ovary tumor, 3 unmatched normal ovary, 1 unmatched mammary tumor and 1 unmatched normal mammary gland are also shown.
  • Table 3 represent a combined total of 140 samples in 18 human tissue types. Sixty-eight samples representing 13 different tissue types excluding prostate had no detected prolOl mRNA (Table 3) . In 4 tissues (stomach small intestine kidney and testis) no prolOl (SEQ ID NO:l) mRNA was detected for any sample tested from individuals (Table 3) . Expression of this PSG was detected in testis in the pooled normal sample (Table 3) . The median expression in prostate cancer samples in Table 3 is 166.5 units. Excluding Ovary 4 (Normal) , only 1 sample in Table 3, Liver 2 (Cancer) , is greater than 10% of this value.
  • SEQ ID NO:l is expressed at higher levels in 9 of 13 (69%) prostate cancer tissues (Prostate 1, 2, 3, 4, 5, 6, 8, 10 and

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Abstract

La présente invention concerne un nouveau procédé de détection, de diagnostic, de surveillance, de stadification et de pronostic du cancer de la prostate.
EP99921946A 1998-05-21 1999-05-12 Nouveau procede de diagnostic, de surveillance et de stadification du cancer de la prostate Withdrawn EP1082460A4 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05019760A EP1621639A3 (fr) 1998-05-21 1999-05-12 Nouveau procédé de diagnostic, de surveillance et de stadification du cancer de la prostate

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US8626598P 1998-05-21 1998-05-21
US86265P 1998-05-21
PCT/US1999/010548 WO1999060162A1 (fr) 1998-05-21 1999-05-12 Nouveau procede de diagnostic, de surveillance et de stadification du cancer de la prostate

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP05019760A Division EP1621639A3 (fr) 1998-05-21 1999-05-12 Nouveau procédé de diagnostic, de surveillance et de stadification du cancer de la prostate

Publications (2)

Publication Number Publication Date
EP1082460A1 true EP1082460A1 (fr) 2001-03-14
EP1082460A4 EP1082460A4 (fr) 2003-02-12

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EP99921946A Withdrawn EP1082460A4 (fr) 1998-05-21 1999-05-12 Nouveau procede de diagnostic, de surveillance et de stadification du cancer de la prostate

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EP (1) EP1082460A4 (fr)
JP (1) JP3677210B2 (fr)
CA (1) CA2328377A1 (fr)
WO (1) WO1999060162A1 (fr)

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Publication number Priority date Publication date Assignee Title
US6902892B1 (en) 1998-10-19 2005-06-07 Diadexus, Inc. Method of diagnosing, monitoring, staging, imaging and treating prostate cancer
US20020004206A1 (en) * 1999-04-09 2002-01-10 Berger Barry M. Methods of screening for disease
US20020048777A1 (en) * 1999-12-06 2002-04-25 Shujath Ali Method of diagnosing monitoring, staging, imaging and treating prostate cancer
AU2002236579A1 (en) * 2000-11-06 2002-05-21 Diadexus, Inc. Compositions and methods relating to prostate specific genes and proteins
WO2002038810A2 (fr) * 2000-11-06 2002-05-16 Diadexus, Inc. Compositions et methodes concernant des genes et des proteines specifiques de la prostate
EP1368471A2 (fr) * 2000-11-21 2003-12-10 Diadexus, Inc. Compositions et procedes se rapportant a des genes et proteines specifiques a la prostate
WO2002042329A2 (fr) * 2000-11-21 2002-05-30 Diadexus, Inc. Compositions et methodes se rapportant a des genes prostatiques specifiques et a des proteines
WO2006047787A2 (fr) 2004-10-27 2006-05-04 Exact Sciences Corporation Methode de surveillance de la progression ou la recurrence d'une maladie
US9777314B2 (en) 2005-04-21 2017-10-03 Esoterix Genetic Laboratories, Llc Analysis of heterogeneous nucleic acid samples

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Title
DATABASE EMBL [Online] Human NKX3.1 gene, 15 October 2002 (2002-10-15) retrieved from EMBL Database accession no. NM_006167 XP002223221 *
DATABASE EMBL [Online] Human NKX3.1 mRNA, 17 December 1996 (1996-12-17) retrieved from EMBL Database accession no. U80669 XP002084746 *
HE W W ET AL: "a novel human prostate-specific androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer" GENOMICS, ACADEMIC PRESS, SAN DIEGO, US, vol. 43, no. 1, 1 July 1997 (1997-07-01), pages 69-77, XP002084749 ISSN: 0888-7543 *
LOPEZ-OTIN CARLOS ET AL: "Breast and prostate cancer: An analysis of common epidemiological, genetic, and biochemical features." ENDOCRINE REVIEWS, vol. 19, no. 4, August 1998 (1998-08), pages 365-396, XP002220464 ISSN: 0163-769X *
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PRESCOTT J L ET AL: "Isolation and androgen regulation of the human homeobox cDNA, NKX3.1" PROSTATE, WILEY-LISS, NEW YORK, NY, US, [Online] vol. 35, no. 1, 1 April 1998 (1998-04-01), pages 71-80, XP002084750 ISSN: 0270-4137 *
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VOELLER H J ET AL: "Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers" CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, BALTIMORE, MD, US, vol. 57, 15 October 1997 (1997-10-15), pages 4455-4459, XP002084751 ISSN: 0008-5472 *

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Publication number Publication date
JP3677210B2 (ja) 2005-07-27
JP2002515263A (ja) 2002-05-28
CA2328377A1 (fr) 1999-11-25
EP1082460A4 (fr) 2003-02-12
WO1999060162A1 (fr) 1999-11-25

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